Zinc inhibits calcium-mediated and nitric oxide-mediated ion secretion in human enterocytes

Canani, Roberto Berni; Secondo, Agnese; Passariello, Annalisa; Buccigrossi, Vittoria; Canzoniero, Lorella M.T.; Ruotolo, S.; Puzone, C.; Porcaro, Francesco; Pensa, Manuela; Braucci, Antonio; Pedata, Monica; Annunziato, Lucio; Guarino, Alfredo

doi:10.1016/j.ejphar.2009.09.042

Cited by 26 publications

(14 citation statements)

References 34 publications

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“…Although an effect of Zn pre‐feeding on secretory pathways was not delineable in the present study, the acute zinc addition in vitro had significant reducing effects on the Cl − secretion induced by PGE 2 , St p and, at least numerically, carbachol. This agrees with several previous studies showing that the presence of zinc at the basolateral side reduces the effect of secretagogues such as 5‐HT, vasoactive intestinal peptide (VIP), theophylline and carbachol in pigs (Carlson et al., ) and carbachol (Berni Canani et al., ) and cholera toxin (Canani et al., ) in Caco‐2 cells. The latter study by Canani et al.…”

Section: Discussionsupporting

confidence: 92%

“…As a possible explanation for the antidiarrhoeal effect of zinc, decreased secretory responses to several secretagogues have been observed when zinc has been applied at the basolateral side of isolated intestinal epithelia (Feng et al., ; Carlson et al., ). However, even this information is contradictory (Canani et al., ; Hoque et al., ; Berni Canani et al., ). Given the inconsistent and sometimes inconclusive results of previous studies, this study aimed at a very systematic and broad‐based approach to assess the effect of dietary zinc supplementation at different dosages on both absorptive and secretory transport properties in the jejunum of piglets of various age groups after weaning.…”

Section: Introductionmentioning

confidence: 99%

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Effects of age and zinc supplementation on transport properties in the jejunum of piglets

Gefeller

Martens

Aschenbach

et al. 2014

Animal Physiology Nutrition

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Zinc is effective in the prevention and treatment of post-weaning diarrhoea and in promoting piglet growth. Its effects on the absorption of nutrients and the secretory capacity of the intestinal epithelium are controversial. We investigated the effects of age, dietary pharmacological zinc supplementation and acute zinc exposure in vitro on small-intestinal transport properties of weaned piglets. We further examined whether the effect of zinc on secretory responses depended on the pathway by which chloride secretion is activated. A total of 96 piglets were weaned at 26 days of age and allocated to diets containing three different levels of zinc oxide (50, 150 and 2500 ppm). At the age of 32, 39, 46 and 53 days, piglets were killed, and isolated epithelia from the mid-jejunum were used for intestinal transport studies in conventional Ussing chambers, with 23 μm ZnSO4 being added to the serosal side for testing acute effects. Absorptive transport was stimulated by mucosal addition of d-glucose or l-glutamine. Secretion was activated by serosal addition of prostaglandin E2 , carbachol or by mucosal application of Escherichia coli heat-stable enterotoxin (Stp ). Jejunal transport properties showed significant age-dependent alterations (p < 0.03). Both absorptive and secretory responses were highest in the youngest piglets (32 d). The dietary zinc supplementation had no significant influence on jejunal absorptive and secretory responses. However, the pre-treatment of epithelia with ZnSO4 in vitro led to a small but significant decrease in both absorptive and secretory capacities (p < 0.05), with an exception for carbachol (p = 0.07). The results showed that, in piglets, chronic supplementation with zinc did not sustainably influence the jejunal transport properties in the post-weaning phase. Because transport properties are influenced by the addition of zinc in vitro, we suggest that possible epithelial effects of zinc depend on the acute presence of this ion.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Effects of age and zinc supplementation on transport properties in the jejunum of piglets

Gefeller

Martens

Aschenbach

et al. 2014

Animal Physiology Nutrition

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“…We confirmed that Zn 2+ reduced the level of cAMP production elicited by forskolin in Caco‐2 cells and rat colonic tissue, suggesting that its mode of action encompasses both K channel blockade as well as interference in cAMP production. Zn 2+ also attenuated production of intracellular calcium and of γ ‐interferon‐stimulated production of NO in Caco‐2, a reasonable conclusion is that, apart from cGMP, the main intracellular mediators responsible for secretion are blocked at the epithelial level by Zn 2+ , depending on concentration, gut region and species [12] …”

Section: Discussionmentioning

confidence: 76%

“…For example, while Zn 2+ attenuated forskolin‐ and carbachol‐stimulated electrogenic chloride secretion in piglet small intestine at low concentrations, data from rat ileum showed that 8‐bromoadenosine cAMP blocked secretion across rat ileum with a very high IC 50 of 0.43 m m , and there was no blockade of secretion stimulated by carbachol [7,9,10] . In contrast, Zn 2+ blocked carbachol‐mediated secretion in Caco‐2 monolayers [12] . In Caco‐2 cells, Zn 2+ also blocked secretion caused by CT, effects that were ascribed to an associated decrease in cAMP levels [11] .…”

Section: Discussionmentioning

confidence: 98%

Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: insights into its antidiarrhoeal actions

Bzik

Medani

Baird

et al. 2012

Journal of Pharmacy and Pharmacology

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“…In previous studies, incubation of Caco-2 cells with Zn 2+ on the serosal, but not mucosal, side reduced intestinal Cl − secretion by blocking basolateral membrane K + channels or via regulation of cAMP or Ca 2+ -dependent pathways [9,16,17,73]. These studies used very high concentration of Zn 2+ (1 mM) or prolonged (>20 min) exposure, which likely induce increases in intracellular Zn 2+ levels and there by modulate multiple signaling pathways that regulate ion transport [74,75].…”

Section: Discussionmentioning

confidence: 99%

The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

Sunuwar

Asraf

Donowitz

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn2+ acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn2+ we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn2+ and ZnR/GPR39 are both required for a beneficial effect of Zn2+ in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl− transport, a critical factor in diarrhea, by upregulating K+/Cl− cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl− absorption pathway. Finally, inhibition of KCC-dependent Cl− transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn2+ acting via ZnR/GPR39 has a direct role in controlling Cl− absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.

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Zinc inhibits calcium-mediated and nitric oxide-mediated ion secretion in human enterocytes

Cited by 26 publications

References 34 publications

Effects of age and zinc supplementation on transport properties in the jejunum of piglets

Effects of age and zinc supplementation on transport properties in the jejunum of piglets

Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: insights into its antidiarrhoeal actions

The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

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